tbuckley/cabot-search huggingface dataset:
Comparison of Injuries Associated With Electric Scooters, Motorbikes, and Bicycles in France, 2019-2022
Authors: Arthur James, Anatole Harrois, Paer-Selim Abback, Jean Denis Moyer, Caroline Jeantrelle, Jean-Luc Hanouz, Mathieu Boutonnet, Thomas Geeraerts, Anne Godier, Julien Pottecher, Delphine Garrigue-Huet, Jean Cotte, Jean Pasqueron, Arnaud Foucrier, Tobias Gauss, Mathieu Raux, Gérard Audibert, Fanny Bounes, Thomas Clavier, Regis Cloche, Benjamin Cohen, Christophe Couturier, Nathalie Delhaye, Jacques Duranteau, Leslie Dussau, Thierry Floch, Nicolas Gatulle, Sébastien Gettes, Pierre Gosset, Olivier Langeron, Marc Leone, Eric Meaudre, Marie Moisan, Jean Pujo, Véronique Ramonda, Julie Rotival, Marie Werner, Mathieu Willig
Journal: JAMA Network Open (2023)

Electric scooter (e-scooter) use is increasing in France and in many urban environments worldwide. Yet little is known about injuries associated with use of e-scooters.
Expression of Concern: Timing of Introduction of Complementary Foods — United States, 2016–2018
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

1) that there was an overestimation in surveillance data of the proportion of children aged 1-5 years who were introduced early (age <4 months) to complementary foods.A U.S. Census Bureau April 2023 data correction technical document describes a data processing error in the National Survey of Children's Health for data collected during 2016-2021 (2).Because of this, the report authors are undertaking a thorough reanalysis using the corrected data.In accordance with December 2017 guidance from the International Committee of Medical Journal Editors (3), this Expression of Concern notice is to alert readers that the reanalysis is currently being conducted to correct the estimates and assess the validity of conclusions in the publication.A corrected report will be published in the coming weeks.
Skipper analysis of eCLIP datasets enables sensitive detection of constrained translation factor binding sites
Authors: Evan A. Boyle, Hsuan-Lin Her, Jasmine R. Mueller, Jack T. Naritomi, Grady G. Nguyen, Gene W. Yeo
Journal: Cell Genomics (2023)

Technology for crosslinking and immunoprecipitation (CLIP) followed by sequencing (CLIP-seq) has identified the transcriptomic targets of hundreds of RNA-binding proteins in cells. To increase the power of existing and future CLIP-seq datasets, we introduce Skipper, an end-to-end workflow that converts unprocessed reads into annotated binding sites using an improved statistical framework. Compared with existing methods, Skipper on average calls 210%-320% more transcriptomic binding sites and sometimes >1,000% more sites, providing deeper insight into post-transcriptional gene regulation. Skipper also calls binding to annotated repetitive elements and identifies bound elements for 99% of enhanced CLIP experiments. We perform nine translation factor enhanced CLIPs and apply Skipper to learn determinants of translation factor occupancy, including transcript region, sequence, and subcellular localization. Furthermore, we observe depletion of genetic variation in occupied sites and nominate transcripts subject to selective constraint because of translation factor occupancy. Skipper offers fast, easy, customizable, and state-of-the-art analysis of CLIP-seq data.
Estimating Patient-Specific Relative Benefit of Adding Biologics to Conventional Rheumatoid Arthritis Treatment
Authors: Yan Luo, Konstantina Chalkou, Satoshi Funada, Georgia Salanti, Toshi A. Furukawa
Journal: JAMA Network Open (2023)

Importance Current evidence remains ambiguous regarding whether biologics should be added to conventional treatment of rheumatoid arthritis for specific patients, which may cause potential overuse or treatment delay. Objectives To estimate the benefit of adding biologics to conventional antirheumatic drugs for the treatment of rheumatoid arthritis given baseline characteristics. Data Sources Cochrane CENTRAL, Scopus, MEDLINE, and the World Health Organization International Clinical Trials Registry Platform were searched for articles published from database inception to March 2, 2022. Study Selection Randomized clinical trials comparing certolizumab plus conventional antirheumatic drugs with placebo plus conventional drugs were selected. Data Extraction and Synthesis Individual participant data of the prespecified outcomes and covariates were acquired from the Vivli database. A 2-stage model was fitted to estimate patient-specific relative outcomes of adding certolizumab vs conventional drugs only. Stage 1 was a penalized logistic regression model to estimate the baseline expected probability of the outcome regardless of treatment using baseline characteristics. Stage 2 was a bayesian individual participant data meta-regression model to estimate the relative outcomes for a particular baseline expected probability. Patient-specific results were displayed interactively on an application based on a 2-stage model. Main Outcomes and Measures The primary outcome was low disease activity or remission at 3 months, defined by 3 disease activity indexes (ie, Disease Activity Score based on the evaluation of 28 joints, Clinical Disease Activity Index, or Simplified Disease Activity Index). Results Individual participant data were obtained from 3790 patients (2996 female [79.1%] and 794 male [20.9%]; mean [SD] age, 52.7 [12.3] years) from 5 large randomized clinical trials for moderate to high activity rheumatoid arthritis with usable data for 22 prespecified baseline covariates. Overall, adding certolizumab was associated with a higher probability of reaching low disease activity. The odds ratio for patients with an average baseline expected probability of the outcome was 6.31 (95% credible interval, 2.22-15.25). However, the benefits differed in patients with different baseline characteristics. For example, the estimated risk difference was smaller than 10% for patients with either low or high baseline expected probability. Conclusions and Relevance In this individual participant data meta-analysis, adding certolizumab was associated with more effectiveness for rheumatoid arthritis in general. However, the benefit was uncertain for patients with low or high baseline expected probability, for whom other evaluations were necessary. The interactive application displaying individual estimates may help with treatment selection.
<i>QuickStats:</i> Age-Adjusted Rates* of Firearm-Related Homicide,† by Race,§ Hispanic Origin, and Sex — National Vital Statistics System, United States, 2021
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Male FemaleDeaths per 100,000 standard population Sex All American Indian or Alaska Native, NH Asian, NH Black or African American, NH White, NH Hispanic or LatinoAbbreviation: NH = non-Hispanic.* Deaths per 100,000 population are age-adjusted to the 2000 U.S. standard population, with 95% CIs indicated by error bars.In 2021, the age-adjusted rate of firearm-related homicide was 11.1 deaths per 100,000 standard population for males and 2.1 for females.† Firearm-related homicides were identified using International Classification of Diseases, Tenth Revision underlying cause-of-death codes U01.4 and X93-X95.§ Race groups are non-Hispanic; persons of Hispanic origin can be of any race.Native Hawaiian or other Pacific Islander persons are not shown separately because of small numbers.All includes all race and Hispanic origin groups including those not shown.Death rates for Asian, American Indian or Alaska Native, and Hispanic or Latino (Hispanic) persons might be affected by misclassification of race and Hispanic origin on death certificates.https://www.cdc.gov/nchs/data/series/sr_02/sr02_172.pdfIn 2021, among males, Black or African American (Black) males had the highest age-adjusted rate of firearm-related homicide (52.9 deaths per 100,000 standard population), and Asian males had the lowest rate (1.5).Among females, Black females had the highest rate (7.5), and Asian females had the lowest rate (0.5).Males had higher rates than females across all race and Hispanic origin groups.
<i>Notes from the Field</i>: Outbreak of Cryptosporidiosis Among Collegiate Swimmers and Evidence of Secondary Transmission — Massachusetts and Rhode Island, 2023
Authors: Geena Chiumento, Anthony Osinski, Kelsey DeVoe, Amelia Houghton, Akita Joshi, Caryn Ivanof, Emma Creegan, Michael Gosciminski, Alexandra P. Newman, Susan Madison-Antenucci, Michele C. Hlavsa, Erin Imada, Colleen Lysen, Shanna Miko, Jordan Schultz, Emily Harvey, Johanna Vostok, Catherine M. Brown
Journal: MMWR Morbidity and Mortality Weekly Report (2023)
Patterns of item nonresponse behaviour to survey questionnaires are systematic and associated with genetic loci
Authors: Gianmarco Mignogna, Caitlin E. Carey, Robbee Wedow, Nikolas Baya, Mattia Cordioli, Nicola Pirastu, Rino Bellocco, Kathryn Fiuza Malerbi, Michel G. Nivard, Benjamin M. Neale, Raymond K. Walters, Andrea Ganna
Journal: Nature Human Behaviour (2023)

Abstract Response to survey questionnaires is vital for social and behavioural research, and most analyses assume full and accurate response by participants. However, nonresponse is common and impedes proper interpretation and generalizability of results. We examined item nonresponse behaviour across 109 questionnaire items in the UK Biobank ( N = 360,628). Phenotypic factor scores for two participant-selected nonresponse answers, ‘Prefer not to answer’ (PNA) and ‘I don’t know’ (IDK), each predicted participant nonresponse in follow-up surveys (incremental pseudo- R 2 = 0.056), even when controlling for education and self-reported health (incremental pseudo- R 2 = 0.046). After performing genome-wide association studies of our factors, PNA and IDK were highly genetically correlated with one another ( r g = 0.73 (s.e. = 0.03)) and with education ( r g,PNA = −0.51 (s.e. = 0.03); r g,IDK = −0.38 (s.e. = 0.02)), health ( r g,PNA = 0.51 (s.e. = 0.03); r g,IDK = 0.49 (s.e. = 0.02)) and income ( r g,PNA = –0.57 (s.e. = 0.04); r g,IDK = −0.46 (s.e. = 0.02)), with additional unique genetic associations observed for both PNA and IDK ( P &lt; 5 × 10 −8 ). We discuss how these associations may bias studies of traits correlated with item nonresponse and demonstrate how this bias may substantially affect genome-wide association studies. While the UK Biobank data are deidentified, we further protected participant privacy by avoiding exploring non-response behaviour to single questions, assuring that no information can be used to associate results with any particular respondents.
The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma
Authors: Cera Nieto, Bettina Miller, Nathaniel Alzofon, Tugy Chimed, Jack Himes, Molishree Joshi, Karina Gomez, Farshad N Chowdhury, Phuong N Le, Alice Weaver, Hilary Somerset, J Jason Morton, Jing H Wang, Xiao-Jing Wang, Dexiang Gao, Kirk Hansen, Stephen B Keysar, Antonio Jimeno
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood. Methods We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1–ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion. To determine how PD-L1 transduces signals intracellularly, we used the BioID2 platform to identify the PD-L1 intracellular interactome. Both human papillomavirus-positive and negative patient-derived xenografts were implanted in NOD-scid-gamma and humanized mouse models to investigate the effects of recombinant PD-1, anti–PD-L1, and anti–signal transducer and activator of transcription 3 (STAT3) in vivo. Results PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell–intrinsic signaling. PD-L1 binding partners interleukin enhancer binding factors 2 and 3 (ILF2-ILF3) transduced their effect through STAT3. Δ260-290PD-L1 disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T-cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control. Conclusions Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T-cell function while simultaneously enhancing cancer cell–invasive properties.
A phase II study of Bruton’s tyrosine kinase inhibition for the prevention of anaphylaxis
Authors: Ragha V. Suresh, Collin Dunnam, Dhananjay Vaidya, Robert A. Wood, Bruce S. Bochner, Donald W. MacGlashan, Melanie C. Dispenza
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDIgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton's tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK inhibitor that is FDA approved to treat some B cell malignancies, in preventing clinical reactivity to peanut in adults with peanut allergy.METHODSAfter undergoing graded oral peanut challenge to establish their baseline level of clinical reactivity, 10 patients had a 6-week rest period, then received 4 standard doses of 100 mg acalabrutinib twice daily and underwent repeat food challenge. The primary endpoint was the change in patients' threshold dose of peanut protein to elicit an objective clinical reaction.RESULTSAt baseline, patients tolerated a median of 29 mg of peanut protein before objective clinical reaction. During subsequent food challenge on acalabrutinib, patients' median tolerated dose significantly increased to 4,044 mg (range 444-4,044 mg). 7 patients tolerated the maximum protocol amount (4,044 mg) of peanut protein with no clinical reaction, and the other 3 patients' peanut tolerance increased between 32- and 217-fold. 3 patients experienced a total of 4 adverse events that were considered to be possibly related to acalabrutinib; all events were transient and nonserious.CONCLUSIONAcalabrutinib pretreatment achieved clinically relevant increases in patients' tolerance to their food allergen, thereby supporting the need for larger, placebo-controlled trials.TRIAL REGISTRATIONClinicalTrials.gov NCT05038904FUNDINGAstraZeneca Pharmaceuticals, the Johns Hopkins Institute for Clinical and Translational Research, the Ludwig Family Foundation, and NIH grants AI143965 and AI106043.
Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model
Authors: Elena Bekerman, Stephen R. Yant, Laurie VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wang, Christian Callebaut
Journal: Journal of Clinical Investigation (2023)

Long-acting antiretroviral agents for preexposure prophylaxis (PrEP) represent a promising new alternative to daily oral regimens for HIV prevention. Lenacapavir (LEN) is a first-in-class long-acting capsid inhibitor approved for the treatment of HIV-1 infection. Here, we assessed the efficacy of LEN for PrEP using a single high-dose simian-human immunodeficiency virus (SHIV) rectal challenge macaque model. In vitro, LEN showed potent antiviral activity against SHIV, as it did for HIV-1. In macaques, a single subcutaneous administration of LEN demonstrated dose proportional increases in and durability of drug plasma levels. A high-dose SHIV inoculum for the PrEP efficacy evaluation was identified via virus titration in untreated macaques. LEN-treated macaques were challenged with high-dose SHIV 7 weeks after drug administration, and the majority remained protected from infection, as confirmed by plasma PCR, cell-associated proviral DNA, and serology testing. Complete protection and superiority to the untreated group was observed among animals whose LEN plasma exposure exceeded its model-adjusted clinical efficacy target at the time of challenge. All infected animals had subprotective LEN concentrations and showed no emergent resistance. These data demonstrate effective SHIV prophylaxis in a stringent macaque model at clinically relevant LEN exposures and support the clinical evaluation of LEN for HIV PrEP in humans.
Illicitly Manufactured Fentanyl–Involved Overdose Deaths with Detected Xylazine — United States, January 2019–June 2022
Authors: Mbabazi Kariisa, Julie O’Donnell, Sagar Kumar, Christine L. Mattson, Bruce A. Goldberger
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

In 2022, provisional data indicated that more than two thirds (68%) of the reported 107,081 drug overdose deaths in the United States involved synthetic opioids other than methadone, principally illicitly manufactured fentanyls (IMFs) (1). Xylazine, a nonopioid sedative not approved for human use and with no known antidote, has been increasingly detected in IMF products in the U.S. drug supply* and in IMF-involved overdose deaths (2). Limited studies suggest xylazine can cause central nervous system depression, respiratory depression, bradycardia, and hypotension in humans (3,4); chronic use might lead to severe withdrawal symptoms† as well as skin ulcerations (4). This report uses data from CDC's State Unintentional Drug Overdose Reporting System (SUDORS) to describe IMF-involved§ overdose deaths with and without xylazine detected that occurred during January 2019-June 2022. Among 21 jurisdictions, which included 20 states and the District of Columbia, the monthly percentage of IMF-involved deaths with xylazine detected increased 276%, from 2.9% to 10.9%. Among IMF-involved deaths during January 2021-June 2022 in 32 jurisdictions, xylazine was detected in a higher percentage of jurisdictions in the Northeast U.S. Census Bureau region; listing detected xylazine as a cause of death varied across jurisdictions. Expanded postmortem and illicit drug product testing for xylazine is needed to clarify prevalence in drug supplies; further investigation of xylazine's effects on humans is necessary to characterize morbidity and overdose risk. It is important for overdose prevention and response messages to highlight the potential presence of xylazine in IMF products and emphasize the need for respiratory and cardiovascular support to address the sedative effects of xylazine.
Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration
Authors: Leon Tejwani, Youngseob Jung, Hiroshi Kokubu, Sowmithra Sowmithra, Luhan Ni, Changwoo Lee, Benjamin Sanders, Paul J. Lee, Yangfei Xiang, Kimberly Luttik, Armand Soriano, Jennifer Yoon, Junhyun Park, Hannah H. Ro, Hyoungseok Ju, Clara Liao, Sofia Massaro Tieze, Frank Rigo, Paymaan Jafar-Nejad, Janghoo Lim
Journal: Journal of Clinical Investigation (2023)

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.
Active transcription in the vascular bed characterizes rapid progression in idiopathic pulmonary fibrosis
Authors: Nirmal S. Sharma, Kapil Patel, Ezgi Sari, Shruti Shankar, Maria G. Gastanadui, Diego Moncada-Giraldo, Yixel Soto-Vazquez, Delores Stacks, Louise Hecker, Kevin Dsouza, Mudassir Banday, Edward O’Neill, Paul Benson, Gregory Payne, Camilla Margaroli, Amit Gaggar
Journal: Journal of Clinical Investigation (2023)
Sharing parental genomes by siblings concordant or discordant for autism
Authors: Mathew Wroten, Seungtai Yoon, Peter Andrews, Boris Yamrom, Michael Ronemus, Andreas Buja, Abba M. Krieger, Dan Levy, Kenny Ye, Michael Wigler, Ivan Iossifov
Journal: Cell Genomics (2023)

Studying thousands of families, we find siblings concordant for autism share more of their parental genomes than expected by chance, and discordant siblings share less, consistent with a role of transmission in autism incidence. The excess sharing of the father is highly significant (p value of 0.0014), with less significance for the mother (p value of 0.31). To compare parental sharing, we adjust for differences in meiotic recombination to obtain a p value of 0.15 that they are shared equally. These observations are contrary to certain models in which the mother carries a greater load than the father. Nevertheless, we present models in which greater sharing of the father is observed even though the mother carries a greater load. More generally, our observations of sharing establish quantitative constraints that any complete genetic model of autism must satisfy, and our methods may be applicable to other complex disorders.